In eukaryotes, all biological functions, including DNA replication, cell cycle progression, energy metabolism, and cell growth and differentiation, are regulated through the reversible phosphorylation of proteins. The phosphorylation state of a protein determines not only its function, subcellular distribution, and stability, but also what other proteins or cellular components it associates with. The balance of specific phosphorylation in the proteome as a whole, as well as of individual members in a biochemical pathway, is thus used by organisms as a strategy to maintain homeostasis in response to an ever-changing environment [Cohen, P. Nat. Rev. Drug Disc., 2002, 1, 309]. The enzymes that carry out these phosphorylation and dephosphorylation steps are protein kinases and phosphatases, respectively. Many kinases have gained importance as drug discovery targets in a variety of therapeutic areas [Fischer, P. M. Curr. Med. Chem., 2004, 11, 1563].
The eukaryotic protein kinase family is one of the largest in the human genome, comprising some 500 genes [Manning, G.; Whyte, D. B.; Martinez, R; Hunter, T.; Sudarsanam, S., The protein kinase complement of the human genome, Science 2002, 298, 1912-1934; Kostich, M.; English, J.; Madison, V.; Gheyas, F.; Wang, L., et al. Human members of the eukaryotic protein kinase family, Genome Biology 2002, 3, Research 0043.0041-0043.0012].
The majority of kinases contain a 250-300 amino acid residue catalytic domain with a conserved core structure. This domain comprises a binding pocket for ATP (less frequently GTP), whose terminal phosphate group the kinase transfers covalently to its macromolecular substrates. The phosphate donor is always bound as a complex with a divalent ion (usually Mg2+ or Mn2+). Another important function of the catalytic domain is the binding and orientation for phosphotransfer of the macromolecular substrate. The catalytic domains present in most kinases are more or less homologous.
A wide variety of molecules capable of inhibiting protein kinase function through antagonising ATP binding are known in the art [Dancey, J.; Sausville, E. A. Issues and progress with protein kinase inhibitors for cancer treatment, Nat. Rev. Drug Disc. 2003, 2, 296-313; Cockerill, G. S.; Lackey, K. E., Small molecule inhibitors of the class 1 receptor tyrosine kinase family. Current Topics in Medicinal Chemistry 2002, 2, 1001-1010; Fabbro, D.; Ruetz, S.; Buchdunger, E.; Cowan-Jacob, S. W.; Fendrich, G. et al., Protein kinases as targets for anticancer agents: from inhibitors to useful drugs, Pharmacol. Ther. 2002, 93, 79-98; Cohen, P., Protein kinases—the major drug targets of the twenty-first century? Nat. Rev. Drug Disc. 2002, 1, 309-315; Bridges, A. J., Chemical inhibitors of protein kinases, Chem. Rev. 2001, 101(8), 2541-2571].
By way of example, the applicant has previously disclosed 2-anilino-4-heteroaryl-pyrimidine compounds with kinase inhibitory properties, particularly against cyclin-dependent kinases (CDKs) [Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Fischer, P. M., N-(4-(4-methylthiazol-5-yl)pyrimidin-2-yl)-N-phenylamines as antiproliferative compounds, PCT Intl. Patent Appl. Publ. WO 2003029248, Cyclacel Limited, UK; Wu, S. Y.; McNae, I.; Kontopidis, G.; McClue, S. J.; McInnes, C. et al., Discovery of a Novel Family of CDK Inhibitors with the Program LIDAEUS: Structural Basis for Ligand-Induced Disordering of the Activation Loop, Structure 2003, 11, 399410; Fischer, P. M.; Wang, S.; Wood, G., Inhibitors of cyclin dependent kinases as anti-cancer agents, PCT Intl. Patent Appl. Pubi. WO 02/079193; Cyclacel Limited, UK; Wang, S.; Fischer, P. M. Anti-cancer compounds, US Patent Appl. Publ. 2002/0019404; Fischer, P. M.; Wang, S., 2-substituted 4-heteroaryl-pyrimidines and their use in the treatment of proliferative disorders, PCTIntl. Patent Appl. Publ. WO 2001072745; Cyclacel Limited, UK].
CDKs are serine/threonine protein kinases that associate with various cyclin subunits. These complexes are important for the regulation of eukaryotic cell cycle progression, but also for the regulation of transcription [Knockaert, M.; Greengard, P.; Meijer, L., Pharmacological inhibitors of cyclin-dependent kinases, Trends Pharmacol. Sci. 2002, 23, 417-425; Fischer, P. Ma; Endicott, J.; Meijer, L., Cyclin-dependent kinase inhibitors, Progress in Cell Cycle Research; Editions de la Station Biologique de Roscoff: Roscoff, France, 2003; pp 235-248].
The present invention seeks to provide further substituted pyrimidine derivatives. More specifically, the invention relates to compounds that have broad therapeutic applications in the treatment of a number of different diseases and/or that are capable of inhibiting one or more protein kinases.